Mast cells and basophils, which are activated by immunoglobulin E (IgE) and allergen, play a prominent role in anaphylaxis. However, they express at least three types of IgE receptors: the high affinity IgE receptor (Fc(epsilon)RI), and the two low affinity IgG receptors (Fc(gamma)RII and Fc(gamma)RIII) also capable of binding IgE. The relative contribution of these, and possibly other receptors such as CD23/Fc(epsilon)RII and Mac- 2, to the genesis of in vivo anaphylaxis is still unclear. To address this question, we have generated mice deficient mice with a disrupted Fc(epsilon)RI alpha chain gene. This defect results in complete suppression of the cell surface expression of Fc(epsilon)RI. These mice appear normal and express a normal number of mast cells, but they are resistant to cutaneous and systemic anaphylaxis. These data demonstrate that Fc(epsilon)RI is necessary for the initiation of IgE-dependent anaphylactic reactions. Therefore, interfering with its function should be an effective means of treating allergy, regardless of the allergen specificity. We are also in the process of generating mice with a disrupted Fc(epsilon)RI beta chain gene. Since the beta chain not only associate with Fc(epsilon)RI but also with Fc(gamma)RIII, these mice should allow us to analyze the contribution of the beta chain in Fc(gamma)RIII-related cell activation.